Preclinical evidence of remote ischemic conditioning in ischemic stroke, a metanalysis update

AbstractRemote ischemic conditioning (RIC) is a promising therapeutic approach for ischemic stroke patients. It has been proven that RIC reduces infarct size and improves functional outcomes. RIC can be applied either before ischemia (pre-conditioning; RIPreC), during ischemia (per-conditioning; RIPerC) or after ischemia (post-conditioning; RIPostC). Our aim was to systematically determine the efficacy of RIC in reducing infarct volumes and define the cellular pathways involved in preclinical animal models of ischemic stroke. A systematic search in three databases yielded 50 peer-review articles. Data were analyzed using random effects models and results expressed as percentage of reduction in infarct size (95% CI). A meta-regression was also performed to evaluate the effects of covariates on the pooled effect-size. 95.3% of analyzed experiments were carried out in rodents. Thirty-nine out of the 64 experiments studied RIPostC (61%), sixteen examined RIPreC (25%) and nine tested RIPerC (14%). In all studies, RIC was shown to reduce infarct volume (− 38.36%; CI − 42.09 to − 34.62%) when compared to controls. There was a significant interaction caused by species. Short cycles in mice significantly reduces infarct volume while in rats the opposite occurs. RIPreC was shown to be the most effective strategy in mice. The present meta-analysis suggests that RIC is more efficient in transient ischemia, using a smaller number of RIC cycles, applying larger length of limb occlusion, and employing barbiturates anesthetics. There is a preclinical evidence for RIC, it is safe and effective. However, the exact cellular pathways and underlying mechanisms are still not fully determined, and its definition will be crucial for the understanding of RIC mechanism of action.

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Remote Ischemic Conditioning With Exercise (RICE)—Rehabilitative Strategy in Patients With Acute Ischemic Stroke: Rationale, Design, and Protocol for a Randomized Controlled Study

Frontiers in Neurology ◽

10.3389/fneur.2021.654669 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhenzhen Han ◽

Wenbo Zhao ◽

Hangil Lee ◽

Melissa Wills ◽

Yanna Tong ◽

...

Keyword(s):

Ischemic Stroke ◽

Adverse Events ◽

Acute Ischemic Stroke ◽

Infarct Volume ◽

Controlled Trial ◽

Walking Ability ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Randomized Controlled ◽

Symptom Exacerbation

Objective: Exercise rehabilitation is an effective therapy in reducing the disability rate after stroke and should be carried out as early as possible. However, very early rehabilitation exercise exacerbates brain injury and is difficult to conduct in stroke patients due to their weakened and potentially disabled state. It is valuable to explore additional early rehabilitation strategies. Remote Ischemic Conditioning (RIC) is a novel therapy designed to protect vital organs from severe lethal ischemic injury by transient sublethal blood flow to non-vital organs, including the distal limbs, in order to induce endogenous protection. RIC has previously been conducted post-stroke for neuroprotection. However, whether combined early RIC and exercise (RICE) therapy enhances stroke rehabilitation remains to be determined.Methods: This is a single-center, double-blinded, randomized controlled trial that will enroll acute ischemic stroke patients within 24 h of symptom onset or symptom exacerbation. All enrolled patients will be randomly assigned to either the RICE group (exercise with RIC) or the control group (exercise with sham RIC) at a ratio of 1:1, with 20 patients in each group. Both groups will receive RIC or sham RIC within 24 h after stroke onset or symptom exacerbation, once a day, for 14 days. All patients will begin exercise training on the fourth day, twice a day, for 11 days. Their neurological function [Modified Rankin Scale (mRS) score, National Institutes of Health Stroke Scale (NIHSS) score, Barthel Index, and walking ability], infarct volume (nuclear magnetic resonance, MRI), and adverse events will be evaluated at different time points in their post-stroke care.Results: The primary outcome is safety, measured by the incidence of any serious RICE-related adverse events and decreased adverse events during hospitalization. The secondary outcome is a favorable prognosis within 90 days (mRS score < 2), determined by improvements in the mRS score, NIHSS score, Barthel Index, walking ability after 90 days, and infarct volume after 12 ± 2 days.Conclusion: This study is a prospective randomized controlled trial to determine the rehabilitative effect of early RIC followed by exercise on patients with acute ischemic stroke.Trial Registration:www.chictr.org.cn, identifier: ChiCTR2000041042

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Remote Ischemic Conditioning May Improve Disability and Cognition After Acute Ischemic Stroke: A Pilot Randomized Clinical Trial

Frontiers in Neurology ◽

10.3389/fneur.2021.663400 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alina Poalelungi ◽

Delia Tulbă ◽

Elena Turiac ◽

Diana Stoian ◽

Bogdan Ovidiu Popescu

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Sham Group ◽

Infarct Volume ◽

Difference Score ◽

Remote Ischemic Conditioning ◽

Median Difference ◽

Ischemic Conditioning ◽

The Difference ◽

Interventional Group

Background and Aim: Remote ischemic conditioning is a procedure purported to reduce the ischemic injury of an organ. This study aimed to explore the efficiency and safety of remote ischemic conditioning in patients with acute ischemic stroke. We hypothesized that remote ischemic conditioning administered from the first day of hospital admission would improve the infarct volume and clinical outcome at 180 days.Material and Methods: We performed a unicentric double-blind randomized controlled trial. We included all patients consecutively admitted to an Emergency Neurology Department with acute ischemic stroke, ineligible for reperfusion treatment, up to 24 hours from onset. All subjects were assigned to receive secondary stroke prevention treatment along with remote ischemic conditioning on the non-paretic upper limb during the first 5 days of hospitalization, twice daily - a blood pressure cuff placed around the arm was inflated to 20 mmHg above the systolic blood pressure (up to 180 mmHg) in the experimental group and 30 mmHg in the sham group. The primary outcome was the difference in infarct volume (measured on brain CT scan) at 180 days compared to baseline, whereas the secondary outcomes included differences in clinical scores (NIHSS, mRS, IADL, ADL) and cognitive/mood changes (MoCA, PHQ-9) at 180 days compared to baseline.Results: We enrolled 40 patients; the mean age was 65 years and 60% were men. Subjects in the interventional group had slightly better recovery in terms of disability, as demonstrated by the differences in disability scores between admission and 6 months (e.g., the median difference score for Barthel was −10 in the sham group and −17.5 in the interventional group, for ADL −2 in the sham group and −2.5 in the interventional group), as well as cognitive performance (the median difference score for MoCA was −2 in the sham group and −3 in the interventional group), but none of these differences reached statistical significance. The severity of symptoms (median difference score for NIHSS = 5 for both groups) and depression rate (median difference score for PHQ-9 = 0 for both groups) were similar in the two groups. The median difference between baseline infarct volume and final infarct volume at 6 months was slightly larger in the sham group compared to the interventional group (p = 0.4), probably due to an initial larger infarct volume in the former.Conclusion: Our results suggest that remote ischemic conditioning might improve disability and cognition. The difference between baseline infarct volume and final infarct volume at 180 days was slightly larger in the sham group.

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Neuroprotection by remote ischemic conditioning in the setting of acute ischemic stroke: a preclinical two-centre study

Scientific Reports ◽

10.1038/s41598-020-74046-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Maryna V. Basalay ◽

Marlene Wiart ◽

Fabien Chauveau ◽

Chloe Dumot ◽

Christelle Leon ◽

...

Keyword(s):

Ischemic Stroke ◽

Infarct Size ◽

Acute Ischemic Stroke ◽

Limb Ischemia ◽

Male Rats ◽

Area At Risk ◽

Neuroprotective Effects ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Secondary Endpoints

Abstract Reperfusion is the only existing strategy for patients with acute ischemic stroke, however it causes further brain damage itself. A feasible therapy targeting reperfusion injury is remote ischemic conditioning (RIC). This was a two-centre, randomized, blinded international study, using translational imaging endpoints, aimed to examine the neuroprotective effects of RIC in ischemic stroke model. 80 male rats underwent 90-min middle cerebral artery occlusion. RIC consisted of 4 × 5 min cycles of left hind limb ischemia. The primary endpoint was infarct size measured on T2-weighted MRI at 24 h, expressed as percentage of the area-at-risk. Secondary endpoints were: hemispheric space-modifying edema, infarct growth between per-occlusion and 24 h MRI, neurofunctional outcome measured by neuroscores. 47 rats were included in the analysis after applying pre-defined inclusion criteria. RIC significantly reduced infarct size (median, interquartile range: 19% [8%; 32%] vs control: 40% [17%; 59%], p = 0.028). This effect was still significant after adjustment for apparent diffusion coefficient lesion size in multivariate analysis. RIC also improved neuroscores (6 [3; 8] vs control: 9 [7; 11], p = 0.032). Other secondary endpoints were not statistically different between groups. We conclude that RIC in the setting of acute ischemic stroke in rats is safe, reduces infarct size and improves functional recovery.

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Abstract P752: Neuroprotection by Remote Ischemic Conditioning in the Setting of Acute Ischemic Stroke: A Preclinical Two-Centre International Study

Stroke ◽

10.1161/str.52.suppl_1.p752 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Maryna V Basalay ◽

Marlene Wiart ◽

Fabien Chauveau ◽

Chloe Dumot ◽

Christelle Leon ◽

...

Keyword(s):

Ischemic Stroke ◽

Infarct Size ◽

Acute Ischemic Stroke ◽

Sample Size Calculation ◽

International Study ◽

Control Group ◽

Inclusion Criteria ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Secondary Endpoints

Background and Purpose: Currently, reperfusion is the only existing treatment strategy for patients with acute ischemic stroke. However, reperfusion may cause further brain damage. One of the feasible therapies targeting reperfusion injury is remote ischemic conditioning (RIC). The main objective of this study was to test the neuroprotective effects of RIC in a rat model of acute ischemic stroke in a randomized and blinded two-centre MRI study with a priori sample size calculation . Methods: Eighty male Sprague Dawley rats underwent 90-min middle cerebral artery occlusion. Multiparametric MRI was performed per-occlusion to ascertain focal cerebral ischemia (inclusion criteria) and to control interindividual variability in the analysis. RIC was started 10 min before reperfusion, and consisted of 4 cycles of 5-min left hind limb ischemia. The primary endpoint of the study was infarct size measured on T2-weighted MRI at 24h, corrected for edema, and expressed as percentage of the area-at-risk of infarction . Secondary endpoints were hemispheric space-modifying edema, infarct growth between per-occlusion and 24h MRI, and neurofunctional outcome measured by neuroscores. Results: Two animals died in each group. In total, 47 rats were included in the analysis after applying the pre-defined inclusion criteria (23 in control group and 24 in RIC group). Infarct size was significantly reduced in the RIC group (mean, interquartile range: 19% [8% ; 32%] vs control: 40% [17% ; 59%], p=0.028). This infarct-limiting effect was still statistically significant after adjustment for apparent diffusion coefficient (ADC) lesion size in multivariate analysis. In the subgroup of rats with ADC lesion > 100 mm3, infarct size reduced from 58% [40%; 66%] to 32% [27%; 40%], p=0.004. In line with this result, RIC significantly improved neuroscores (6 [3 ; 8] vs control: 9 [7 ; 11], p=0.032). The other secondary endpoints were not statistically different between groups. Conclusions: RIC in the setting of acute stroke in rats is safe, reduces infarct size and improves functional recovery in a two-centre international study using translational imaging endpoints.

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